Atherosclerosis, restenosis and immune disorders, such as arthritis, are viewed as inflammatory conditions mediated in large part by an inflammatory cascade. For instance, the pathogenesis of atherosclerosis or restenosis occurs in three phases; an inflammatory phase, a cellular proliferative phase, and a phase of remodeling involving extracellular matrix protein synthesis. The inflammatory phase is initiated by expression and exhibition of inflammatory molecules (such as VCAM-1, ICAM-1, or E-selectin) on endothelial cells, resulting in the recruitment of monocytes from the bloodstream into the sub-endothelial space. When in the endothelium, monocytes transform into macrophages and become foam cells as they take up cholesterol. These cholesterol-loaded foam cells release cytokines such as monocyte-colony stimulating factor and monocyte chemoattractant protein-1 (MCP-1), instigating the cellular proliferative phase. Cytokine secretion results in localized monocyte and smooth muscle cell (SMC) proliferation and recruitment and production of extracellular matrix (the final phase). During this phase macrophages continue their uptake of cholesterol in the form of oxidized low-density lipoprotein resulting in swelling of the artery wall. Continuance of this inflammatory cascade eventually results in the formation of a plaque consisting of lipid-engorged macrophage-foam cells, smooth muscle cells, and extracellular matrix (Crowther M (2005) Hematology 1, 436).
Expression of vascular adhesion molecule-1 (VCAM-1) on the surface of endothelial cells for the adhesion and transmigration of monocytes is a fundamental early event in a wide variety of inflammatory conditions: such as autoimmune disorders, bacterial and viral infections, asthma, rheumatoid arthritis, and autoimmune diabetes, in addition to atherosclerosis (Pilewski J M et al. (1995) Am J Respir Cell Mol Biol 12, 1; Ohkawara Y et al. (1995) Am J Respir Cell Mol Biol 12, 4; Rabb A et al. (1994) Am J Respir Care Med 11, 149). Thus, drugs that inhibit VCAM-1 expression are desirable therapeutics for the treatment of these conditions.
Chemoattractant factors, such as MCP-1, have been shown to play a role in monocyte recruitment, proliferation, and migration in a number of inflammatory conditions and are correlated with a risk for restenosis (Welt F G P et al. (2002) Arterioscler Thromb Vasc Biol. 22, 1769). As such, inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics. Finally, smooth muscle cell hyperplasia, resulting in tissue remodeling and decreased organ function is another characteristic of many inflammatory conditions including atherosclerosis, restenosis, chronic transplant rejection, and asthma. Therefore, inhibition of the hyperproliferation of SMC is another desirable property for therapeutic compounds.
To date the most effective means of preventing and treating atherosclerosis has been via cholesterol-dependant approaches. These include seeking to lower low-density lipoprotein or raise high density lipoprotein cholesterol. For example, one method provides compounds useful for regulating the expression of ApolipoproteinA-I (ApoA-I) (PCT/US2005/038048) a lipoprotein important for transporting cholesterol.
However, the identification of new inflammatory mediators in the early pathogenesis of atherosclerosis and restenosis has led to a new focus on a variety of inflammatory or cholesterol-independent approaches; including the inhibition of VCAM-1 and MCP-1 expression, or prevention of smooth muscle cell (SMC) proliferation. Increasing evidence from epidemiological, clinical, and basic mechanistic studies supports the importance of these inflammatory targets in the treatment and prevention of inflammatory conditions. Finding drugs that inhibit VCAM-1 and/or MCP-1 expression, or inhibit smooth muscle cell proliferation is desirable.
One class of such compounds thought to play a role in the prevention of inflammatory conditions are polyphenols. These are common constituents in of the human diet; they are present in many foods and beverages of plant origin. Numerous patents and applications describe uses, compositions, and methods for the prevention, treatment or mitigation of inflammatory and cardiovascular diseases by the administration of naturally occurring polyphenols to a patient in need of a pharmaceutical intervention (see, e.g., U.S. Ser. Nos. 03/033,578, 10/696,752, US 2004 0105817, U.S. Pat. Nos. 6,900,241, 6,649,193, US 2002 029088, US 2003 065505, PCT/09901997/IB, PCT/00000392/AU, PCT/00235153/US, PCT/US1996/04,028, US 2005 0171163 A1).
It is believed that polyphenols are effective, at least in part, as a result of their activity on the inhibition of VCAM-1, MCP-1, LDL oxidation, and smooth muscle cell proliferation (Takahahi. R et al., (2005) J Agric Food Chem 53, 1; Fuhrman B et al. (2005) J Nutr 135, 722; Cald U P et al. (1996) Am J Clin Nutr 63, 403; Tijburg L B et al. (1997) Crit. Rev Food Sci Nutr 37, 771; Leiro J et al. (2004) Int Immunopharmacol 4, 991; Carluccio M A et al., (2003) Arterioscler Thromb Vasc 23, 622; Ouyang P et al. (2004) Di Yi Jun Yi Da Xue Xue Bao 24, 975; Hofmann C S et al. (2003) FASEB J 17, 702; Araim O et al. (2002) J Vasc. Surg 35, 1226; El Bedout J et al., (2005) Cardiovasc Res 67, 317). The inverse relationship between dietary polyphenol consumption and incidence of cardiovascular diseases is likely associated with their ability to attenuate biomarkers of oxidative stress, lipidemia and inflammation. Consequently, naturally occurring polyphenols have the potential to be therapeutically employed.
However, the protective properties of naturally occurring polyphenols have been difficult to realize for several reasons, including poor bioavailability and deleterious effects at, high concentrations. For instance, the most abundant and available source of resveratrol for consumers, red wine, cannot be consumed in therapeutically efficacious quantities on a daily basis because of the deleterious effects of excessive alcohol consumption. Furthermore, the use of naturally occurring polyphenols as potential therapies has also been impeded by an inability to achieve efficacious levels because of poor bioavailability. Bioavailability of polyphenols in humans ranges from 1% to 26% with variability between individuals, and between different polyphenols. In addition to this, polyphenols differ in how they are absorbed, metabolized, and excreted. For example, polyphenol flavonoids, such as quercetin, have been reported to have less than 1% intestinal absorption following oral administration (Gugler et al. (1975) Eur J Clin Pharm 9, 223). Another complicating factor is the effect of metabolites of polyphenols. These have been shown to have a negative influence on the biological activity of the parent compounds. Such metabolites often differ from the parent compound in terms of toxicity, efficacy, and length of residence in the plasma. These and other limiting factors, such as poor water solubility limiting the route of administration, have made it difficult to determine appropriate dosages for use in humans.
Additionally, several human studies on foods or beverages containing polyphenols have failed to demonstrate any significant benefit on primary clinical endpoints, such as oxidative stress, lipidemia, and inflammation. Of twelve recent studies examining differing sources of polyphenols; six showed no effect on lipid parameters while the other six showed some improvement (Manach (2005) Curr Opin Lipidol 16, 77-84). Such contradictory data has limited the use of polyphenols, despite their many potentially beneficial properties.
Thus, there continues to be a need for novel compounds with properties like those of polyphenols for the prevention and treatment of inflammatory conditions. Embodiments of the present invention include compounds that inhibit VCAM-1 and/or MCP-1 expression and/or inhibit smooth muscle cell proliferation. The compounds of the present invention also possess other properties, which enable their use in the treatment or prophylaxis of other diseases and conditions.